Asthma is associated with increased severity and duration of rhinitis: A study with the Allergic Rhinitis and its Impact on Asthma classes in the Constances cohort

Abstract Background Few population‐based studies have described allergic rhinitis (AR) according to the Allergic Rhinitis and its Impact on Asthma (ARIA) classification, and none have assessed the impact of asthma on this classification. Our aims were to 1) describe AR according to four ARIA classes and 2) within each of the four ARIA classes, compare participants with AR alone versus those with AR and asthma. Methods Cross‐sectional analyses were performed using data from the 2014 annual follow‐up questionnaire of the French adult population‐based cohort Constances. Current AR was defined by the report of sneezing, runny, or blocked nose in the last 12 months and the report of nasal allergies. Following ARIA recommendations, rhinitis was classified according to its severity (mild or moderate‐severe) and duration (intermittent or persistent). Ever asthma was also defined by a questionnaire. Results Among the 4675 participants with AR (57% women, mean age 50.2 ± 12.7 years), 44% were classified as mild/intermittent, 16% mild/persistent, 25% moderate‐severe/intermittent, and 15% moderate‐severe/persistent. Within each of the four ARIA classes, compared to participants with rhinitis alone, participants with rhinitis and asthma had significantly more severe symptoms, more conjunctivitis, a higher mean eosinophil count and more treatments with intra‐nasal corticosteroids and oral antihistamines co‐medication. Conclusions This is a paradigm shift study as for the first time this large population‐based study in adults showed that asthma status has a profound effect on the ARIA classification. Rhinitis alone and rhinitis with asthma represent two distinct phenotypes. These results reinforce the need to include asthma status in the ARIA classification and guidelines.


| INTRODUCTION
Allergic rhinitis (AR) is one of the most prevalent diseases in the world. 1 All countries, ethnicities, and age groups are affected by AR, leading to a global health problem. 2 In this context, during a World Health Organization workshop in 1999, the Allergic Rhinitis and Its Impact on Asthma (ARIA) initiative was initiated.The first ARIA report published in 2001 3 as a major document for the classification and management of rhinitis was updated or revised in 2008, 2 2010, 4 2016 5 and 2022.7][8] Several population-based studies have described AR according to its duration [9][10][11][12] or severity [12][13][14][15] but none have investigated the duration and severity together.In a previous study based on data from the Constances population-based cohort, we observed a much higher prevalence of mild AR than in clinical practice, 16 suggesting the existence of rhinitis profiles with different characteristics in the general population, in particular regarding rhinitis severity.Another gap in the literature concerns whether the co-occurrence of asthma may impact the characteristics of the different AR classes: even if it is known that asthma and AR often coexist, no study has investigated the impact of asthma in the ARIA classification.Furthermore, a recent hypothesis proposed that rhinitis alone is a disease distinct from rhinitis with asthma. 17Overall, no population-based study has been conducted in adults to describe AR according to its severity and duration or to assess if within each of the four ARIA class participants with AR alone are different from those with AR and asthma.
Our aim was to describe AR according to its severity and duration defined by the ARIA classification among adults from the general population.Our specific objectives were to 1) describe AR according to four ARIA classes and 2) within each of the four ARIA classes, compare participants with AR alone versus those with AR and asthma.

| Study design
A cross-sectional study was carried out with the data from the 2014 annual follow-up questionnaire of the Constances cohort among participants reporting current AR.We first describe AR according to the two major criteria of ARIA that is, severity and duration and then we studied the impact of asthma on these ARIA classes concerning clinical features, eosinophils and medication needs.

| AR and asthma
As specific Immunoglobulin E (IgE) and Skin Prick Tests (SPTs) are not available in Constances, we used a definition of AR based on a questionnaire, as published previously. 16,21Participants were considered as having current AR if they answered "yes" to all the three following questions: "During your lifetime, have you ever had a problem with sneezing, or a runny, or a blocked nose when you did not have a cold or the flu?", to "Have you had these problems in the last 12 months?",and to "Have you ever had nasal allergies in your lifetime, including hay fever?".
Following the ARIA recommendations, 2 AR was defined as moderate-severe if at least one of the symptoms of rhinitis: rhinorrhea, nasal congestion, nasal pruritus, or sneezing has been reported  as a disturbing problem affecting daily activities and sleep.Otherwise, rhinitis was defined as mild if none of the symptoms have been reported as a disturbing problem affecting daily activities and sleep.
Allergic rhinitis was defined as persistent if symptoms occurred more than 4 days per week and more than four consecutive weeks.
Otherwise, AR was defined as intermittent.
Participants were considered as having ever-asthma if they answered yes to "Have you ever had asthma?" at inclusion or answered "asthma" to: "Here is a list of health problems.Indicate here the ones you have suffered from in the last 12 months (whether or not there was a work interruption, whether or not there is a treatment)" at the 2014 follow-up questionnaire.
Other variables of interest are described in the supplement.

| Statistical analyses
Analysis in complete-cases, that is, by excluding participants with missing data, was carried out, and no imputation was performed.
We described AR according to the ARIA classification of severity (mild versus moderate-severe) and duration (intermittent versus persistent) separately.The severity and duration of rhinitis were then combined into four classes according to the ARIA classification: mild/ intermittent, mild/persistent, moderate-severe/intermittent, and moderate-severe/persistent.Then, we compared participants with AR and never asthma versus those with AR and ever asthma within each of the four ARIA classes.
Pearson Chi-2 tests for categorical variables and Student t test/ analysis of variance comparison of variances for continuous variables were used.We computed effect size measures. 22For categorical variables (Cramer's V coefficient), values of 0.1-0.3 were considered to represent small effect sizes, 0.3-0.5 medium effect and ≥0.5 large effect sizes. 23For continuous variables (Cohen's D coefficient), values of 0.2-0.5 were considered to represent small effect sizes, 0.5-0.8medium effect and ≥0.8 large effect sizes. 24We performed additional analyses with multivariate logistic regressions comparing participants with ever asthma to those with never asthma among the different strata of ARIA classification, adjusting for age, gender, smoking, diploma, conjunctivitis and eczema.
All analyses were performed using SAS 9.4 software (SAS Institute).

| Demographic characteristics of the participants
Among the 26,737 participants included in the cohort by 2013, 21,507 (80%) of them completed the 2014 follow-up questionnaire.
Participants with missing data regarding the definition of AR (n = 735) were excluded from the analyses.Among participants with current AR, participants with missing data regarding severity (n = 1031), duration (n = 100), or ever asthma (n = 91) were also excluded.Finally, 4584 participants with AR were included (Figure 1).
Compared to participants with missing data for severity and duration, participants included in the analyses were younger and had a higher level of education (Table S1).

| AR duration
The characteristics of participants with AR according to its duration are presented in Table 3.No significant differences were observed for gender, age, smoking status, education level and body mass index between groups.Participants with persistent AR had a higher mean eosinophil count (222.1 vs. 203.4,p = 0.001), a higher TNSS4 (6.4 vs. 5.6, p < 0.0001) and reported more moderate-severe rhinitis (49.0% vs. 35.9%,p < 0.0001) than those with intermittent AR.Participants with persistent AR also reported more ever asthma (28.3% vs. 23.9%,p = 0.002) and ever conjunctivitis (58.2% vs. 53.0%,p = 0.002).

| AR according to the four classes ARIA classification
The characteristics of participants with AR according to the four ARIA classes are presented in Table 4.The four classes had different characteristics: participants with mild AR, whether it was intermittent or persistent, had the lowest prevalences for ever asthma (21.2%), ever conjunctivitis (50.6%), and ever eczema (37.4%), the highest proportion of participants with neither OA nor INCS (43.7%), and the lowest mean eosinophil count (201 � 138).In contrast, participants with moderate-severe/persistent AR had the highest prevalences for ever asthma (34.1%), ever conjunctivitis (63.4%), and ever eczema (46.3%), the highest proportion of participants with comedication (OA þ INCS) (52.3%), and the highest mean eosinophil count (235 � 188).Participants with mild/persistent rhinitis had the latest age of onset of symptoms and a higher percentage of participants reported not knowing what triggered their symptoms.In contrast, participants with moderate-severe/persistent rhinitis had the earliest age of onset of symptoms and a lower percentage of participants reporting not knowing what triggered their symptoms.
F I G U R E 1 Flow chart.Among the 26,737 participants included in the cohort by 2013, 21,507 (80%) of them completed the 2014 followup questionnaire.Participants with missing data regarding the definition of allergic rhinitis (AR) (n = 735) were excluded from the analyses.Among participants with current AR, participants with missing data regarding severity (n = 1031), duration (n = 100), or ever asthma (n = 91) were also excluded.Finally, 4584 participants with AR were included in the present analysis.

| Influence of asthma on the ARIA classification
Eight sub-classes were defined according to the ARIA classification and the ever asthma status in each subclass (Table 5), with the number of participants per subclass ranging from 166 (mild/ persistent AR with ever asthma) to 1590 (mild/intermittent AR without ever asthma).
Whatever the ARIA subclass considered, within each ARIA subclass, asthma multimorbidity further separated participants, showing significant differences for most outcomes.In particular, ever conjunctivitis was higher by 10%-20% in AR and ever asthma in comparison to AR alone for all 4 ARIA classes (small effect size).In each category, the largest effect size between participants without ever asthma and with ever asthma was for the age of onset of rhinitis.
The age of onset of rhinitis ranged from 16.1 years (moderate-severe/intermittent AR þ ever asthma) to 26.0 years (mild/intermittent AR alone).Importantly, co-medication (OA þ INCS) was reported from 18.8% (mild intermittent AR alone) to 64.1% (moderate-severe AR þ ever asthma).The prevalence of reported symptoms was always higher in the AR þ ever asthma group regardless of the ARIA class.Reported triggers of rhinitis symptoms were far higher in AR þ ever asthma than AR alone for mites or house dust and animals.
Eosinophil counts were significantly higher for all ARIA classes in participants with asthma than in those with rhinitis alone (small to medium effect sizes).Of note, mean eosinophil counts varied little across the ARIA classes in participants without asthma (range from 192 to 203 cells/mm 3 ), but more marked differences between classes were observed in participants with ever asthma (range from 231 to 291 cells/mm 3 ).The results of the multivariate logistic regressions after adjustment for age, gender, smoking, diploma, conjunctivitis and eczema are presented in the Table S2.Overall, the strength of the effects and the significance were the same as in the unadjusted analyses.

| DISCUSSION
For the first time in a population-based study in adults, AR has been described according to the four classes of ARIA classification.More symptoms, conjunctivitis, and eczema were associated with moderate-severe AR.Asthma prevalence, treatments and reports of rhinitis triggers were higher for participants with moderate-severe and/or persistent rhinitis.Considering asthma status provided additional information to the ARIA classification.The major finding is that within each of the four ARIA classes, compared to participants with rhinitis alone, participants with rhinitis and asthma had significantly more severe nasal symptoms, more conjunctivitis, higher mean eosinophil count, and more need for INCS and OA co-medication.

| Strengths and limitations
Constances is the largest French population-based epidemiological study in adults, presenting in 2014 a detailed questionnaire on rhinitis which allowed us to describe in detail the characteristics of AR according to the ARIA classification.Constances is however not fully representative of the French adult population as 1) participants were randomly selected from the affiliated of the National Health T A B L E 1 Demographic characteristics, and allergic rhinitis and its impact on asthma (ARIA) classification of participants with allergic rhinitis (AR).

Analysis population (n = 4584)
Sex, n (%) Insurance Fund ("Caisse nationale d'assurance maladie", CNAM).In France, the General Health Insurance Fund administered by CNAM is compulsory for salaried workers, even during unemployed periods and their families; it covers about 85% of the population living in France.Individuals not covered by this scheme are those belonging to the agricultural scheme, which provides social protection for farmers and agricultural workers, the schemes for the liberal professions, and special schemes (such as those for the French National Railway Company).As a result, some of the workers associated with these professions could not be included in Constances.2) some geographical areas of France were not included.In addition, about 20% of participants had missing data for rhinitis severity.Compared to the participants included in the analysis population, the participants with missing data had a lower level of education and a higher average age, and we cannot exclude that they may have a particular rhinitis profile.
As specific IgE and SPTs are not available in Constances, we used a definition of AR based on a questionnaire.We acknowledge that defining AR by questionnaire may be considered a limitation, even if we have used validated and standardized questions. 25We recently showed that the definition we have used is a suitable proxy for AR, 21 and we found the known characteristics of AR using this definition in Constances. 16These questions have the advantage of being based on the main symptoms of AR and are understandable to all participants, which allows all rhinitis to be considered, even those that have not been diagnosed by a doctor.This is especially important as many patients with mild symptoms do not consult a doctor for their rhinitis.
Although the questionnaire-based definition of asthma could be perceived as a limitation, it is important to note that many previous epidemiological studies have already used and validated our definitions based on the European community respiratory health survey questionnaire. 25,26

| Interpretation
1.9][30] This is not surprising as it is known that patients who consult a health professional are mainly those with severe symptoms.Few population-based studies have estimated the prevalence of rhinitis according to its severity.Participants with moderate-severe AR reported a higher TNSS4 score as compared to those with mild AR, as previously reported in the literature. 8,31Similar to Antonicelli et al., 32 in our study, the participants with mild rhinitis reported less treatment than those with moderate-severe rhinitis.In four previous studies, [12][13][14][15] the prevalence of moderate to severe rhinitis ranged from 56% to 87%, which is higher than the prevalence observed in our study; however, the differences in AR definitions across studies make comparisons difficult.
2. Severity impacts more the characteristics of AR than duration, as shown by the higher effect sizes observed for severity than for duration.This was already observed in patients consulting for rhinitis in primary care. 27Thus, (i) the treatment strategy should be based on severity.This is reflected by real-world data obtained from an app showing that European patients treat themselves according to symptoms 33 (ii) Duration is important for its T A B L E 5 Characteristics of allergic rhinitis (AR) according to the allergic rhinitis and its impact on asthma (ARIA) classification and asthma status., n (%)

Moderate
An annual follow-up was done through a postal or online self-questionnaire.The annual follow-up questionnaires present different questions each year, according to specific research themes.One of the themes of the 2014 annual follow-up questionnaire was rhinitis.All participants who were included until the end of 2013 received the 2014 annual follow-up questionnaire, which included two pages of detailed, validated, and standardized questions on rhinitis (online supplement).All confidentiality, safety and security procedures were approved by the French legal authorities.Approvals were obtained from the National Data Protection Authority on March 3, 2011 (Commission Nationale de l'Informatique et des Libertés-CNIL, French National Data Protection Authority (authorisation no.910486)), the National Council for Statistical Information (Conseil National de l'Information Statistique-CNIS), the National Medical Council (Conseil National de l'Ordre des Médecins-CNOM), and the Institutional Review Board of the National Institute for Medical Research-INSERM (authorisation no.01-011).All participants signed a written informed consent.

Table 1
Characteristics of allergic rhinitis (AR) according to the allergic rhinitis and its impact on asthma (ARIA) classification.